More is not always better: finding the right trade-off between affinity and selectivity of a G-quadruplex ligand. Issue 19 (9th July 2018)

• Record Type: Journal Article
• Authors: Zuffo, Michela; Guédin, Aurore; Leriche, Emma-Dune; Doria, Filippo; Pirota, Valentina; Gabelica, Valérie; Mergny, Jean-Louis; Freccero, Mauro
• Is Part Of: Nucleic acids research. Volume 46:Issue 19(2018)
• Page Start: e115
• Page End: e115
• Publication Date: 2018-07-09
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gky607
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Guanine-rich nucleic acid sequences can fold into four-stranded G-quadruplex (G4) structures. Despite growing evidence for their biological significance, considerable work still needs to be done to detail their cellular occurrence and functions. Herein, we describe an optimized core-extended naphthalene diimide (cex -NDI) to be exploited as a G4 light-up sensor. The sensing mechanism relies on the shift of the aggregate-monomer equilibrium towards the bright monomeric state upon G4 binding. In contrast with the majority of other ligands, this novel cex -NDI is able to discriminate among G4s with different topologies, with a remarkable fluorescent response for the parallel ones. We investigate this sensing by means of biophysical methods, comparing the lead compound to a non-selective analogue. We demonstrate that mitigating the affinity of the binding core for G4s results in an increased selectivity and sensitivity of the fluorescent response. This is achieved by replacing positively charged substituents with diethylene glycol (DEG) side chains. Remarkably, the limit of detection values obtained for parallel G4s are more than one order of magnitude lower than those of the parallel-selective ligand N -methyl mesoporphyrin IX (NMM). Interestingly, the classical fluorescent intercalator displacement (FID) assay failed to reveal binding of cex -NDI to G4 because of the presence a ternary complex (G4-TO-cex -NDI) revealed by electrospray-MS. Our study thus provides a rational basis to design or modify existent scaffolds to redirect the binding preference of G4 ligands.